The activity of transcriptional factor NRF2 (nuclear factor (erythroid-derived 2)-like 2) is tightly regulated by the cytoplasmic inhibitor KEAP1 (Kelch-like ECH associated protein 1), which acts as an adaptor protein for Cul3-based ubiquitin E3 ligase complex (Joshi and Johnson, 2012; Jung and Kwak, 2010; Tong et al., 2006). KEAP1 (iNRF2) is a cysteine-rich protein that serves as a redox sensor in cells. Under stress conditions, such as an increase of reactive oxygen species (ROS), a group of KEAP1 cysteines are oxidatively modified and the resulting conformational change protects NRF2 from KEAP1-directed degradation (Tong et al., 2007). When NRF2 accumulates in the cytosol to levels that surpass the endogenous sequestration capacity of KEAP1, the excess NRF2 translocates to the nucleus, binds to antioxidant response elements (AREs) in the promoter of target genes, and activates broadly protective responses (Kensler et al., 2007; Lee et al., 2003).
Activation of the NRF2 pathway appears to be impacted in Huntington Disease (HD) systems, based on the findings of altered levels of downstream targets of NRF2 in HD brain (Sorolla et al., 2008), reduced NRF2 activity in HD cell lines (Jin et al., 2013) and neuroprotective effects following NRF2 overexpression (Tsevtkov et al, Nat. Chem. Biol. Jul. 21, 2013 in press). Several upstream signal transduction pathways, including MAPK/ERK/JNK and PI3K regulate NRF2 activation (Cheung et al., 2013) and have been implicated in HD (Apostol et al., 2006). These upstream pathways, stimulated by oxidative stress, phosphorylate NRF2, preventing KEAP1/CUL3 complex from mediating Ub-proteosome degradation (Cullinan et al., 2004).